@article{ceb8c64242fd4d47b57f6039a7fbb7ef,
title = "Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy",
abstract = "Notch signaling is a highly conserved intercellular pathway with tightly regulated and pleiotropic roles in normal tissue development and homeostasis. Dysregulated Notch signaling has also been implicated in human disease, including multiple forms of cancer, and represents an emerging therapeutic target. Successful development of such therapeutics requires a detailed understanding of potential on-target toxicities. Here, we identify autosomal dominant mutations of the canonical Notch ligand Jagged1 (or JAG1) as a cause of peripheral nerve disease in 2 unrelated families with the hereditary axonal neuropathy Charcot-Marie-Tooth disease type 2 (CMT2). Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening. Our studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Together, our findings highlight a critical role for JAG1 in maintaining peripheral nerve integrity, particularly in the recurrent laryngeal nerve, and provide a basis for the evaluation of peripheral neuropathy as part of the clinical development of Notch pathway-modulating therapeutics.",
author = "Sullivan, {Jeremy M.} and Motley, {William W.} and Johnson, {Janel O.} and Aisenberg, {William H.} and Marshall, {Katherine L.} and Barwick, {Katy E.S.} and Lingling Kong and Huh, {Jennifer S.} and Saavedra-Rivera, {Pamela C.} and McEntagart, {Meriel M.} and Marion, {Marie Helene} and Hicklin, {Lucy A.} and Hamid Modarres and Baple, {Emma L.} and Farah, {Mohamed H.} and Zuberi, {Aamir R.} and Lutz, {Cathleen M.} and Rachelle Gaudet and Traynor, {Bryan J.} and Crosby, {Andrew H.} and Sumner, {Charlotte J.}",
note = "Funding Information: We thank the families for their participation in this study, Kenneth (Kurt) Fischbeck and Christy Ludlow for their help enrolling family 1, and Minoru Tada for providing JAG1 plasmids. This work was supported by NIH–National Institute of Neurological Disorders and Stroke (NIH-NINDS) R01NS062869, the Intramural Research Program of the NIH, NINDS intramural research funds, the National Institute on Aging (Z01-AG000949-02), the Medical Research Council (G1002279), and The Jackson Laboratory{\textquoteright}s Genetic Engineering Technologies Scientific Service. WWM was supported in part by NIH-NINDS R25NS065729 and WHA by NIH-NINDS F31NS105404. Funding Information: Authorship note: JMS and WWM are co–first authors. Conflict of interest: WWM is currently an employee of Third Rock Ventures. JOJ is currently an employee of Quest Diagnostics. BJT has received grant support from Merck and Microsoft Research. BJT holds European Union (EP2751284A1, Method For Diagnosing A Neurodegenerative Disease) and US (20180187262) patents on clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of the C9orf72 gene. CJS has received grant support from and holds patents (WO2016/164896 “Modulation of SMN expression,” WO2017/21884 “Combinations for the Modulation of SMN expression”) with Ionis Pharmaceuticals; has served as a paid advisor, consultant, and/or speaker for Biogen, PTC Therapeutics, Roche/Genentech, AveXis, and Cy-tokinetics; and is an associate editor for the JCI. This arrangement has been approved by Johns Hopkins University in accordance with its conflict of interest policies. Copyright: {\textcopyright} 2020, American Society for Clinical Investigation. Submitted: February 13, 2019; Accepted: December 12, 2019; Published: February 17, 2020. Reference information: J Clin Invest. 2020;130(3):1506–1512. https://doi.org/10.1172/JCI128152. Publisher Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",
year = "2020",
month = mar,
day = "2",
doi = "10.1172/JCI128152",
language = "English (US)",
volume = "130",
pages = "1506--1512",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "3",
}